Advances in cancer gene therapy

It is well established that most cancers result from a series of accumulated, acquired genetic lesions in somatic cells that are faithfully reproduced until a malignant clone is created, which is ultimately able to destroy the host. To a larger and larger extent, the genetic lesions associated with malignant transformation and progression in a wide variety of human cancers are being identified. Armed with this knowledge of the molecular anatomy of the cancer cell, gene therapy has emerged as a new method of therapeutic and possibly preventive intervention against cancer targeted at the level of cellular gene expression. This review highlights current strategies and significant developments being employed in gene therapy for neoplastic diseases. Three main approaches currently being investigated are mutation compensation, molecular chemotherapy, and genetic immunotherapy. Mutation compensation relies on strategies to ablate activated oncogenes at the level of DNA (triplex), messenger RNA (antisense or ribozyme) or protein (intracellular single chain antibodies), and augment tumour suppresser gene expression. Molecular chemotherapy uses the delivery of a toxin gene to tumour cells for eradication. This can be accomplished by either transductional targeting, whereby the toxin is specifically delivered to the tumour, or by transcriptional targeting, whereby tumour specific transcriptional activators are employed to selectively 'turn on' the toxin gene exclusively within the tumour. Genetic immunotherapy refers to the treatment based upon the induction of a specific immune response against tumour associated antigens (TAAs). The main objective of this therapy is to reinforce and bolster the immune system of the cancer-bearing host resulting in rejection of the tumour. In this context, for each of these conceptual approaches, human clinical protocols have entered testing in Phase I, II and III to assess dose escalation, safety, and toxicity issues, and more recently to evaluate efficacy, respectively.